The long-term objectives of this project are to investigate the arrhythmogenic mechanisms responsible for sudden cardiac death in patients with coronary heart disease and ventricular hypertrophy, two disorders accounting for the vast majority of the 300,000 annual sudden cardiac deaths in the U.S. Our overall theme is that structural abnormalities of the myocardium that affect cell-to-cell communication lead to electrophysiological disturbances responsible for the fatal ventricular tachyarrhythmia. Some of these abnormalities, once identified, can be corrected or modified, with a corresponding decrease in the risk of arrhythmia. We hypothesize that the autonomic nervous system is an important modulator of cell-to-cell communication and that understanding its role will provide insight into the events that precipitate sudden cardiac death, into understanding the receptive myocardial substrate, into identifying the patients at risk, and into selecting therapeutic options. We plan a series of studies investigating autonomic innervation invasively and noninvasively in individuals with normal hearts, those with coronary artery disease and patients with ventricular hypertrophy. We plan to image sympathetic and vagal myocardial patterns using positron emission tomography. These clinical studies will be tied very closely with the animal experiments. It is anticipated that the result of this project will expand our knowledge of how normal and abnormal autonomic cardiac innervation produces or prevents cardiac arrhythmias and sudden cardiac death.